The cysteine proteases caspase-8 (alternatively named FLICE1/MACH1), caspase 9 (alternatively named Apaf 3/Mch6) and caspase-10 (alternatively named FLICE2/MACH 2) are related proteins that share homology with the prototypic member of the larger caspase gene family, interleukin-1β-converting enzyme (ICE)/caspase 1 (Muzio et al., J. Biol. Chem., 1998, 273:2926–2930; Boldin et al., Cell, 1996, 85:803–815; Srinivasula et al., J. Biol. Chem., 1996, 271:27099–27106; Orth et al., J. Biol. Chem., 1996, 271:20977–20980; Scaffidi et al., EMBO J., 1998, 17:1675–1687; Vincenz et al., J. Biol. Chem.,1997, 272:6578–6583; and Schulz et al., 1994, Cell, 76:145–155). At least thirteen caspases have been identified thus far, and they are responsible for the proteolytic cascade that is essential for some aspects of apoptosis, including membrane blebbing and DNA degradation (Cryns et al., Genes and Devel., 1998, 12:1551–1570). Caspases 8, 9, and 10 are the only known members of this family that contain duplicated death effector domains (DEDs) in a long pro-domain in their amino terminus that precedes the cysteine protease catalytic domain in their carboxyl terminus. The DEDs allow caspase-8 to interact directly with an adaptor molecule, FADD, that also contains a DED. FADD, in turn, contains a death domain (DD) that allows it to directly associate with a number of cell death receptors (e.g., Fas, DR3).
Caspase-8, along with the adapter molecule FADD, is part of the death inducing signaling complex (DISC) associated with the Fas receptor (Medema, et al., EMBO J., 1997, 16:2794–2804). It is activated by autoproteolytic cleavage following recruitment to the receptor through its interaction with the DED of FADD, which allows caspase-8 to form aggregates (Scaffidi et al., EMBO J., 1998, 17:1675–1687; Yang et al., Molecular Cell, 1998, 1:319–325; Muzio et al., supra, 1998). These laboratories have shown that this oligomerization plays an important role in initiating the proper processing of the caspase itself, ultimately leading to an active caspase enzyme. Similarly, the DEDs of caspase 9 allow it to be recruited to a complex with Apafs 1 and 2, where its oligomerization leads to autocatalytic activation as well (Liu et al., Cell, 1997, 89:175–184; Srinivasula et al., supra, 1998). Thus, caspases 8 and 9 are located upstream of all other caspases and their effector function is responsible for the activation of the “caspase cascade”, and subsequent cell death, that occurs following Fas/DR3/TNFR1 activation and release of cytochrome c from mitochondria. Such important apoptotic signaling molecules may be likely targets for disregulation/alteration during tumorigenesis.